Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation

Zhaolu Kong, Daxing Xie, Thomas Boike, Pavithra Raghavan, Sandeep Burma, David J. Chen, Amyn A. Habib, Arup Chakraborty, Jer Tsong Hsieh, Debabrata Saha

Research output: Contribution to journalArticle

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Abstract

DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase-activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90% of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60% of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G2-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G2-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens.

Original languageEnglish (US)
Pages (from-to)2829-2839
Number of pages11
JournalCancer Research
Volume70
Issue number7
DOIs
StatePublished - Apr 1 2010

Fingerprint

Ionizing Radiation
Prostatic Neoplasms
Down-Regulation
Gene Expression
Proteins
Prostate
G2 Phase Cell Cycle Checkpoints
Apoptosis
GTPase-Activating Proteins
Radiation Dosage
Double-Stranded DNA Breaks
Caspase 9
Caspase 8
Caspase 3
Cell Survival
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. / Kong, Zhaolu; Xie, Daxing; Boike, Thomas; Raghavan, Pavithra; Burma, Sandeep; Chen, David J.; Habib, Amyn A.; Chakraborty, Arup; Hsieh, Jer Tsong; Saha, Debabrata.

In: Cancer Research, Vol. 70, No. 7, 01.04.2010, p. 2829-2839.

Research output: Contribution to journalArticle

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title = "Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation",
abstract = "DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase-activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90{\%} of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60{\%} of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G2-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G2-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens.",
author = "Zhaolu Kong and Daxing Xie and Thomas Boike and Pavithra Raghavan and Sandeep Burma and Chen, {David J.} and Habib, {Amyn A.} and Arup Chakraborty and Hsieh, {Jer Tsong} and Debabrata Saha",
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AU - Kong, Zhaolu

AU - Xie, Daxing

AU - Boike, Thomas

AU - Raghavan, Pavithra

AU - Burma, Sandeep

AU - Chen, David J.

AU - Habib, Amyn A.

AU - Chakraborty, Arup

AU - Hsieh, Jer Tsong

AU - Saha, Debabrata

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